Novel nonsense mutation in the hypoxanthine guanine phosphoribosyltransferase gene and nonrandom X-inactivation causing Lesch-Nyhan syndrome in a female patient

Hum Mutat. 1996;7(1):52-8. doi: 10.1002/(SICI)1098-1004(1996)7:1<52::AID-HUMU7>3.0.CO;2-R.


Lesch-Nyhan (LN) disease is a severe X-linked recessive neurological disorder associated with a loss of hypoxanthine guanine phosphoribosyltransferase activity (HPRT, EC We have studied the second example of a female patient with LN disease. The molecular basis of HPRT deficiency in this patient was a previously undescribed nucleotide substitution in exon 6. In this gene, designated HPRT PARIS, a single nucleotide substitution from T to G at base position 558 changed a tyrosine (TAT) to a codon STOP (TAG) (Y153X). Analysis of the mother revealed a normal sequence of the HPRT cDNA and demonstrated that this mutation arose through a de novo gametic event. Allele-specific amplification of exon 6 from the patient's genomic DNA confirmed the single base substitution and showed that the patient was heterozygous for this mutation. Investigation of X-chromosomal inactivation by comparison of methylation patterns of patient's DNA isolated from fibroblasts, T lymphocytes, and polymorphonuclear cells digested with PstI and BstXI, with or without HpaII, and hybridized with M27 beta probe indicated a nonrandom pattern of X-chromosomal inactivation in which there was preferential inactivation of the maternal allele. The data indicate that nonrandom X-inactivation leading to selective inactivation of the maternal gene and a de novo point mutation in the paternal gene were responsible for the lack of HPRT activity in this patient.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Cells, Cultured
  • Dosage Compensation, Genetic*
  • Exons
  • Female
  • Fibroblasts / ultrastructure
  • Genetic Carrier Screening
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / genetics*
  • Lesch-Nyhan Syndrome / genetics*
  • Male
  • Molecular Sequence Data
  • Point Mutation*
  • Polymerase Chain Reaction
  • Restriction Mapping


  • Hypoxanthine Phosphoribosyltransferase